Alzheimer's disease is the most common form of senile dementia and the fourth highest cause of disability and death in the elderly. It is characterized by the presence of three main brain hallmarks viz. diffuse neuronal loss with a particular involvement of the cholinergic system, extracellular protein deposits (amyloid-beta plaques) and intracellular protein deposits (neurofibrillary tangles, NFTs). All current therapies are based on the cholinergic hypothesis and demonstrate only symptomatic treatment. Progression of the disease is not slowed or halted, with symptoms continuing to deteriorate over time. The amyloid hypothesis proposes that Alzheimer's disease is caused by an imbalance between Aβ production and clearance, resulting in increased amounts of Aβ in various forms such as monomers, oligomers, insoluble fibrils and plaques in the CNS. The rate of Aβ production is same as that in healthy volunteers; whereas rate of clearance is impaired by 25-30%. The high levels of Aβ then initiates the cascade of events culminating in neuronal damage and death manifesting as progressive dementia of the Alzheimer's disease type. Evidence shows that insufficient clearance of the Aβ protein from the brain is a prime cause in over 95% of Alzheimer's disease patients (Mawuenyega, K. G. et al. Science 2010, 330, 1774). Further, it is known that Aβ efflux is mediated by p-glycoprotein efflux pump. The p-glycoprotein deficiency at the blood brain barrier increases Aβ deposition in an Alzheimer's disease (Cirrito, J. R. et al., J. Clin. Invest. 2005, 115, 3285). P-glycoprotein (Pgp) is highly expressed on the luminal surface of brain capillary endothelial cells and contributes to the BBB. In Pgp-null mice, [125I]-Aβ40 and [125I]-Aβ42 microinjected into the CNS clear at half the rate than in WT mice. When amyloid precursor protein-transgenic (APP-transgenic) mice were administered Pgp inhibitor, Aβ levels within the brain interstitial fluid significantly increased within hours of treatment. APP-transgenic, Pgp-null mice had increased levels of brain Aβ and enhanced Aβ deposition compared with APP-transgenic, Pgp WT mice. These reports indicate a direct link between Pgp and Aβ metabolism in vivo and suggest that Pgp activity at the BBB could affect risk for developing Alzheimer's disease as well as provide a novel diagnostic and therapeutic target (Lam, F. C. et al., J. Neurochem. 2001, 76, 1121). Thus, it is evident that drugs that have ability to increase levels of Pgp should increase amyloid-beta clearance.
Phloroglucinols widely occur in nature in various plants including plants of Myrtaceae family. Colupulone, a triprenylatated acylphloroglucinol compound isolated from Humulus lupulus (Hops) is reported to display potent PXR activation activity. Another compound of this class, hyperforin isolated from Hypericum perforatum (St. John's Wort) also possess potent PXR activation and Pgp-induction activity. Garcinol (1a) and isogarcinol (2a) are polyprenylated phloroglucinol compounds isolated from Indian medicinal plant Garcinia indica (Rao, A. V. R et al., Tetrahedron Lett. 1980, 21, 1975; Krishnamurthy, N. and Ravindranath, B. Tetrahedron Lett. 1982, 23, 2233). A wide range of pharmacological activities (including anticancer, antiinflammatory, etc) have been reported for Garcinia indica as well as its chemical constituents (Tosa, H. et al., Chem. Pharm. Bull. 1997, 45, 418; Rukachaisirikul, V. et al., Chem. Pharm. Bull. 2005, 53, 342; Pan, M. H. et al., J. Agric. Food Chem. 2001, 49, 1464; Koeberle, A. et al., Biochem. Pharmacol. 2009, 77, 1513; Tian, Z. et al., PLoS One 2011, 6, e21370); however they are never been evaluated as Pgp inducers. In the present invention, the inventors disclose a new series of polyprenylated alkyl and acyl-phloroglucinol compounds as well as their activity as potent Pgp inducers. The novel compounds of the present invention exhibit potent Pgp activity and also do not show cytotoxicity.
